Regional microstructural organization of the cerebral cortex is affected by preterm birth.

Objectives: To compare regional cerebral cortical microstructural organization between preterm infants at term-equivalent age (TEA) and healthy full-term newborns, and to examine the impact of clinical risk factors on cerebral cortical micro-organization in the preterm cohort. Study design: We prospectively enrolled very preterm infants (gestational age (GA) at birth\u3c32 \u3eweeks; birthweight\u3c1500 \u3eg) and healthy full-term controls. Using non-invasive 3T diffusion tensor imaging (DTI) metrics, we quantified regional micro-organization in ten cerebral cortical areas: medial/dorsolateral prefrontal cortex, anterior/posterior cingulate cortex, insula, posterior parietal cortex, motor/somatosensory/auditory/visual cortex. ANCOVA analyses were performed controlling for sex and postmenstrual age at MRI. Results: We studied 91 preterm infants at TEA and 69 full-term controls. Preterm infants demonstrated significantly higher diffusivity in the prefrontal, parietal, motor, somatosensory, and visual cortices suggesting delayed maturation of these cortical areas. Additionally, postnatal hydrocortisone treatment was related to accelerated microstructural organization in the prefrontal and somatosensory cortices. Conclusions: Preterm birth alters regional microstructural organization of the cerebral cortex in both neurocognitive brain regions and areas with primary sensory/motor functions. We also report for the first time a potential protective effect of postnatal hydrocortisone administration on cerebral cortical development in preterm infants

Levels of soluble fms-like tyrosine kinase one in first trimester and outcomes of pregnancy: a systematic review

Angiogenic factors are involved in formation of new blood vessels required for placental development and function; and critical for fetal growth and development. Soluble fms-like tyrosine kinase 1(sFlt-1) is an anti-angiogenic protein that inhibits formation of new blood vessels resulting in potential pregnancy complications. The objective of this study was to undertake a systematic review to assess levels of sFlt-1 in early pregnancy and association with adverse pregnancy outcomes. PubMed and Medline databases and reference lists were searched up to July 2010. Inclusion criteria were pregnant women, blood sample taken during first trimester and assessment/reporting of sFlt-1 concentrations and subsequent pregnancy complications. Twelve relevant studies were identified of 71 to 668 women. No pooling of results was undertaken due to variation in sFlt-1 concentrations (range, 166-6,349 pg/ml amongst controls), samples used (serum, plasma), different summary statistics (mean, median, odds ratio) and outcome definitions applied. Levels of sFlt-1 were generally higher among women who developed preeclampsia (11 studies) or gestational hypertension (two studies), but not significantly different to normotensive women in most studies. There was no consistent pattern in association between sFlt-1 concentrations and fetal growth restriction (4 studies); and levels were non-significantly higher for women with postpartum bleeding (1 study) and significantly lower for stillbirths (1 study).This review found no clear evidence of an association between sFlt-1 levels in first trimester and adverse pregnancy outcomes. However, findings were affected by methodological, biological and testing variations between studies; highlighting the need for consistent testing of new biomarkers and reporting of outcome measures

Developing a risk profile for spontaneous preterm birth and short interval to delivery among patients with threatened preterm labor

BACKGROUND: Threatened preterm birth is the most common reason for antepartum hospitalization in the United States, accounting for approximately 50% of these admissions. However, fewer than 10% of patients with inpatient evaluation for signs or symptoms of preterm labor ultimately deliver before term. OBJECTIVE: This study aimed to generate predictive models to assess the risk of preterm delivery and time to delivery based on clinical signs and symptoms of patients evaluated in our institution for preterm labor concerns. STUDY DESIGN: This was a retrospective cohort study of singleton pregnancies evaluated for signs and/or symptoms of preterm labor, including contractions, abdominal pain, vaginal bleeding, and short cervix, between 22 0/7 and 33 6/7 weeks of gestation. Inpatient evaluations were classified by patient presentation: (1) symptomatic with cervical findings (transvaginal cervical length of \u3c2.5 cm or cervical dilation of \u3e= 2.0 cm), (2) asymptomatic with cervical findings, and (3) symptomatic without cervical findings. The primary outcomes included incidence of spontaneous preterm birth and interval from presentation to delivery, compared between groups. The risk of preterm delivery was evaluated using logbinomial regression, and presentation to delivery timing was assessed by survival analysis and Cox proportional hazards modeling. RESULTS: Of 631 patients with preterm labor concerns, 96 (16%) were symptomatic with cervical findings on evaluation, 51 (8%) were asymptomatic with cervical findings, and 466 (76%) were symptomatic without cervical findings. The occurrence of preterm birth was significantly higher among symptomatic patients with cervical findings (49%) than among those with cervical findings alone (31%) or symptoms alone (11%) (P\u3c.0001). In addition, symptomatic patients with cervical findings were significantly more likely to deliver within 48 hours (20%), 1 week (30%), 2 weeks (33%), and 1 month (43%) of presentation than patients with cervical findings alone (2%, 2%, 6%, and 10%, respectively) or symptoms alone (0.4%, 1%, 1.5%, and 5%, respectively) (P value for trend\u3c.0001). Adjusted for gestational age at presentation and previous preterm birth, the overall risk of preterm delivery was significantly higher among patients with symptoms and cervical findings than among patients with cervical findings alone (relative risk, 2.81; 95% confidence interval, 1.74-4.54) or symptoms alone (relative risk, 4.39; 95% confidence interval, 3.16 -6.09). Adjusted for the same variables, symptomatic patients with cervical findings were also at higher risk of delivery over time after assessment than patients with cervical findings alone (hazard ratio, 2.06; 95% confidence interval, 1.47-2.90) or symptoms alone (hazard ratio, 2.16; 95% confidence interval, 1.74-2.70). The negative predictive value of these models suggested that only 1% of patients with isolated symptoms or cervical findings are at risk of preterm delivery within 1 week of initial presentation. CONCLUSION: Symptomatic patients with cervical findings suggestive of preterm labor were at the greatest risk of preterm birth and a shorter interval from presentation to delivery. The study findings supported a risk profile that may facilitate the selection of patients most appropriate for admission and targeted management. Nonetheless, as nearly 50% of patients meeting this risk profile subsequently deliver at term, future research is needed to identify which of these patients will require intervention

Assessing the Relationship of Patient Reported Outcome Measures With Functional Status in Dysferlinopathy: A Rasch Analysis Approach

Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R2 0.18). EK scores were strongly associated with PUL (Pseudo R2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy

A Qualitative Investigation of Californian Youth Interests in the Outdoors

Prior research has found connections between youth participation in recreational activities and academic achievement, civic involvement, and improved health. To investigate California youth outdoor recreation attitudes, behaviors, and constraints, eight focus groups were conducted with community recreation center youth participants. Youth answered 10 questions about their experiences, attitudes, and perceptions of outdoor recreation. Data were analyzed using grounded theory. Three to seven axial codes were identified for each question. Results showed that youth want to have more access to outdoor recreational activities. However, there are frequently considerable constraints for the youth to overcome including draws of technology, family obligations, and laziness. Safety was a recurring concern among participants. Understanding youth attitudes and perceptions allows managers to meet youth needs, program for youth interests, and provides a strong foundation for marketing and as a rational for funding grants

Assessing Dysferlinopathy Patients Over Three Years With a New Motor Scale

The Jain COS Consortium.[Objective] Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD.[Methods] We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories.[Results] The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline.[Interpretation] The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967–978The estimated US $4 million needed to fund this study was provided by the Jain Foundation. (www.jain-foundation.org) The Jain COS consortium would like to thank the study participants and their families for their invaluable contribution. The John Walton Centre Muscular Dystrophy Research Centre is part of the MRC Centre for Neuromuscular Diseases (Grant number MR/K000608/1).Peer reviewe

Assessment of disease progression in dysferlinopathy: A 1-year cohort study

ObjectiveTo assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.MethodsOne hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis.ResultsThe functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint.ConclusionCertain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials.ClinicalTrials.gov identifier:NCT01676077

Table_2_Assessing the Relationship of Patient Reported Outcome Measures With Functional Status in Dysferlinopathy: A Rasch Analysis Approach.docx

Appendix B. Coinvestigators - The Jain COS Consortium.Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R2 0.18). EK scores were strongly associated with PUL (Pseudo R2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy.Peer reviewe

Assessing dysferlinopathy patients over three years with a new motor scale

OBJECTIVE: Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD. METHODS: We collected a longitudinal series of functional assessments from 187 dysferlinopathy patients over three years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and non-ambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories. RESULTS: The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3-8 years post symptom onset at baseline. INTERPRETATION: The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinics practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy